Metabolites as novel biomarkers for childhood obesity-related traits in Mexican-American children.

BACKGROUND/OBJECTIVES: Although newer approaches have identified several metabolites associated with obesity, there is paucity of such information in paediatric populations, especially among Mexican-Americans (MAs) who are at high risk of obesity. Therefore, we performed a global serum metabolite screening in MA children to identify biomarkers of childhood obesity. METHODS: We selected 15 normal-weight, 13 overweight and 14 obese MA children (6-17 years) and performed global serum metabolite screening using ultra-performance liquid chromatography/quadruple orthogonal acceleration time of flight tandem micro mass spectrometer. Metabolite values were analysed to assess mean differences among groups using one-way analysis of variance, to test for linear trend across groups and to examine Pearson's correlations between them and seven cardiometabolic traits (CMTs): body mass index, waist circumference, systolic blood pressure, diastolic blood pressure, homeostasis model of assessment-insulin resistance, triglycerides and high-density lipoprotein cholesterol. RESULTS: We identified 14 metabolites exhibiting differences between groups as well as linear trend across groups with nominal statistical significance. After adjustment for multiple testing, mean differences and linear trends across groups remained significant (P < 5.9 × 10(-5) ) for L-thyronine, bradykinin and naringenin. Of the examined metabolite-CMT trait pairs, all metabolites except for 2-methylbutyroylcarnitine were nominally associated with two or more CMTs, some exhibiting significance even after accounting for multiple testing (P < 3.6 × 10(-3) ). CONCLUSIONS: To our knowledge, this study - albeit pilot in nature - is the first study to identify these metabolites as novel biomarkers of childhood obesity and its correlates. These findings signify the need for future systematic investigations of metabolic pathways underlying childhood obesity.

Brain-derived neurotrophic factor in human subjects with function-altering melanocortin-4 receptor variants.

BACKGROUND: In rodents, hypothalamic brain-derived neurotrophic factor (BDNF) expression appears to be regulated by melanocortin-4 receptor (MC4R) activity. The impact of MC4R genetic variation on circulating BDNF in humans is unknown. OBJECTIVE: The objective of this study is to compare BDNF concentrations of subjects with loss-of-function (LOF) and gain-of-function (GOF) MC4R variants with those of controls with common sequence MC4R. METHODS: Circulating BDNF was measured in two cohorts with known MC4R sequence: 148 subjects of Pima Indian heritage ((mean±s.d.): age, 15.7±6.5 years; body mass index z-scores (BMI-Z), 1.63±1.03) and 69 subjects of Hispanic heritage (10.8±3.6 years; BMI-Z, 1.57±1.07). MC4R variants were characterized in vitro by cell surface expression, receptor binding and cyclic AMP response after agonist administration. BDNF single-nucleotide polymorphisms (SNPs) rs12291186, rs6265 and rs7124442 were also genotyped. RESULTS: In the Pima cohort, no significant differences in serum BDNF was observed for 43 LOF subjects versus 65 LOF-matched controls (age, sex and BMI matched; P=0.29) or 20 GOF subjects versus 20 GOF-matched controls (P=0.40). Serum BDNF was significantly associated with genotype for BDNF rs12291186 (P=0.006) and rs6265 (P=0.009), but not rs7124442 (P=0.99); BDNF SNPs did not interact with MC4R status to predict serum BDNF. In the Hispanic cohort, plasma BDNF was not significantly different among 21 LOF subjects, 20 GOF subjects and 28 controls (P=0.79); plasma BDNF was not predicted by BDNF genotype or BDNF-x-MC4R genotype interaction. CONCLUSIONS: Circulating BDNF concentrations were not significantly associated with MC4R functional status, suggesting that peripheral BDNF does not directly reflect hypothalamic BDNF secretion and/or that MC4R signaling is not a significant regulator of the bulk of BDNF expression in humans.

Waist circumference is genetically correlated with incident Type 2 diabetes in Mexican-American families.

AIMS: We aimed to determine the genetic and environmental correlation between various anthropometric indexes and incident Type 2 diabetes with a focus on waist circumference. METHODS: We used the data on extended Mexican-American families (808 subjects, 7617.92 person-years follow-up) from the San Antonio Family Heart Study and estimated the genetic and environmental correlations of 16 anthropometric indexes with the genetic liability of incident Type 2 diabetes. We performed bivariate trait analyses using the solar software package. RESULTS: All 16 anthropometric indexes were significantly heritable (range of heritabilities 0.24-0.99). Thirteen indexes were found to have significant environmental correlation with the liability of incident Type 2 diabetes. In contrast, only anthropometric indexes consisting of waist circumference (waist circumference, waist-hip ratio and waist-height ratio) were significantly genetically correlated (genetic correlation coefficients: 0.45, 0.55 and 0.44, respectively) with the liability of incident Type 2 diabetes. We did not observe such a correlation for BMI. CONCLUSIONS: Waist circumference as a predictor of future Type 2 diabetes is supported by the finding that they share common genetic influences.

Localization of a major susceptibility locus influencing preterm birth.

Preterm birth (PTB) is a complex trait, but little is known regarding its major genetic determinants. The objective of this study is to localize genes that influence susceptibility to PTB in Mexican Americans (MAs), a minority population in the USA, using predominantly microfilmed birth certificate-based data obtained from the San Antonio Family Birth Weight Study. Only 1302 singleton births from 288 families with information on PTB and significant covariates were considered for genetic analysis. PTB is defined as a childbirth that occurs at <37 completed weeks of gestation, and the prevalence of PTB in this sample was 6.4%. An ∼10 cM genetic map was used to conduct a genome-wide linkage analysis using the program SOLAR. The heritability of PTB was high (h(2) ± SE: 0.75 ± 0.20) and significant (P = 4.5 × 10(-5)), after adjusting for the significant effects of birthweight and birth order. We found significant evidence for linkage of PTB (LOD = 3.6; nominal P = 2.3 × 10(-5); empirical P = 1.0 × 10(-5)) on chromosome 18q between markers D18S1364 and D18S541. Several other chromosomal regions (2q, 9p, 16q and 20q) were also potentially linked with PTB. A strong positional candidate gene in the 18q linked region is SERPINB2 or PAI-2, a member of the plasminogen activator system that is associated with various reproductive processes. In conclusion, to our knowledge, perhaps for the first time in MAs or US populations, we have localized a major susceptibility locus for PTB on chromosome 18q21.33-q23.

Olfactomedin-like 3 (OLFML3) gene expression in baboon and human ocular tissues: cornea, lens, uvea, and retina.

BACKGROUND: Olfactomedin-like is a family of polyfunctional polymeric glycoproteins. This family has at least four members. One member of this family is OLFML3, which is preferentially expressed in placenta but is also detected in other adult tissues including the liver and heart. However, its orthologous rat gene is expressed in the iris, sclera, trabecular meshwork, retina, and optic nerve. METHODS: OLFML3 messenger amplification was performed by RT-PCR from human and baboon ocular tissues. The products were cloned and sequenced. RESULTS: We report OLFML3 expression in human and baboon eye. The full coding DNA sequence has 1221 bp, from which an open reading frame of 406 amino acid was obtained. The baboon OLFML3 gene nucleotidic sequence has 98% and amino acidic 99% similarity with humans. CONCLUSIONS: OLFML3 gene expression in human and baboon ocular tissues and its high similarity make the baboon a powerful model to deduce the physiological and/or metabolic function of this protein in the eye.

Genetic variation in SH3-domain GRB2-like (endophilin)-interacting protein 1 has a major impact on fat mass.

OBJECTIVE: The SH3-domain GRB2-like (endophilin)-interacting protein 1 (SGIP1) gene has been shown to be differentially expressed in the hypothalamus of lean versus obese Israeli sand rats (Psammomys obesus), and is suspected of having a role in regulating food intake. The purpose of this study was to assess the role of genetic variation in SGIP1 in human disease. SUBJECTS: We performed single-nucleotide polymorphism (SNP) genotyping in a large family pedigree cohort from the island of Mauritius. The Mauritius Family Study (MFS) consists of 400 individuals from 24 Indo-Mauritian families recruited from the genetically homogeneous population of Mauritius. We measured markers of the metabolic syndrome, including diabetes and obesity-related phenotypes such as fasting plasma glucose, waist:hip ratio, body mass index and fat mass. RESULTS: Statistical genetic analysis revealed associations between SGIP1 polymorphisms and fat mass (in kilograms) as measured by bioimpedance. SNP genotyping identified associations between several genetic variants and fat mass, with the strongest association for rs2146905 (P=4.7 × 10(-5)). A strong allelic effect was noted for several SNPs where fat mass was reduced by up to 9.4% for individuals homozygous for the minor allele. CONCLUSIONS: Our results show association between genetic variants in SGIP1 and fat mass. We provide evidence that variation in SGIP1 is a potentially important determinant of obesity-related traits in humans.

A quantitative trait locus on chromosome 5p influences d-dimer levels in the san antonio family heart study.

Background. D-dimer is associated with increasing severity of atherosclerosis and with increased risk of a cardiovascular disease (CVD). Methods and Results. To better understand this risk factor, we performed a genome scan on 803 (301 males and 502 females) Mexican Americans in the San Antonio Family Heart Study (SAFHS). The SAFHS is ideal for the discovery of quantitative trait loci (QTLs) influencing CVD because CVD risk factors are prevalent in Mexican Americans of San Antonio and because the study design involves large families, which is optimal for QTL discovery. D-dimer levels were normalized in our study. We found that D-dimer levels were heritable, at about 23% heritability (P ≈ .00001). In a linkage analysis employing 432 microsatellite markers, we found strong evidence of a QTL on chromosome 5p with a lod score of 3.32 at 21 centiMorgans (cM). We also found suggestive evidence of a QTL on chromosome 2q with a lod score of 2.33 at 207 cM. Conclusions. To our knowledge, the putative QTL on chromosome 5p is novel. The possible QTL on chromosome 2q is discussed in relation to a recent report of linkage of a related hemostatic factor to the same location. These results warrant further investigation.

Pleiotropic effects on subclasses of HDL, adiposity, and glucose metabolism in adult Alaskan Eskimos.

The aim of this study was to analyze the heritability and the presence of pleiotropic effects on subfractions of high-density lipoproteins (HDLs) as measured by nuclear magnetic resonance (NMR), parameters for adiposity, and glucose metabolism in adult Alaskan Eskimos. The present family study included 1,214 adult Alaskan Eskimos (537 male/677 female). Body weight, height, circumferences, selected skinfolds, and blood pressure were measured in all participants. Blood samples were collected under fasting conditions for the isolation of plasma. Glucose, insulin, subclasses and size of lipoproteins, triglycerides, total, and HDL cholesterol and lipoprotein (a) were measured in plasma. HbA1c was measured in total blood. Univariate and bivariate quantitative genetic analyses were conducted between HDL subclasses and size and the anthropometric and biochemical measures using the variance decomposition approach. Variation in all the analyzed traits exhibits a significant genetic component. Heritabilities ranged between 0.18 +/- 0.11 for LDL(2) (intermediate) and 0.89 +/- 0.07 for small HDL. No common genetic effects were found on the HDL subclasses (small, intermediate, and large). Small HDL particles were genetically correlated with LDL particles and HbA1c. Negative genetic correlations were observed between intermediate and large HDL subfractions, HDL size and measures of adiposity, and LDL and parameters for glucose metabolism (HbA1, insulin). These observations confirm the presence of possible pleiotropic effects on HDL, adiposity, and cardiovascular risk factors and provide novel insight on the relationship between HDL subclasses, adiposity, and glucose regulation.

Feto-placental adaptations to maternal obesity in the baboon.

Maternal obesity is present in 20-34% of pregnant women and has been associated with both intrauterine growth restriction and large-for-gestational age fetuses. While fetal and placental functions have been extensively studied in the baboon, no data are available on the effect of maternal obesity on placental structure and function in this species. We hypothesize that maternal obesity in the baboon is associated with a maternal inflammatory state and induces structural and functional changes in the placenta. The major findings of this study were: 1) decreased placental syncytiotrophoblast amplification factor, intact syncytiotrophoblast endoplasmic reticulum structure and decreased system A placental amino acid transport in obese animals; 2) fetal serum amino acid composition and mononuclear cells (PBMC) transcriptome were different in fetuses from obese compared with non-obese animals; and 3) maternal obesity in humans and baboons is similar in regard to increased placental and adipose tissue macrophage infiltration, increased CD14 expression in maternal PBMC and maternal hyperleptinemia. In summary, these data demonstrate that in obese baboons in the absence of increased fetal weight, placental and fetal phenotype are consistent with those described for large-for-gestational age human fetuses.

Cross-species replication of a resistin mRNA QTL, but not QTLs for circulating levels of resistin, in human and baboon.

Resistin has been associated with inflammation and risk for cardiovascular disease. We previously reported evidence of a QTL on chromosome 19p13 affecting the abundance of resistin (RETN) mRNA in the omental adipose tissue of baboons (L0D score 3.8). In this study, whole genome transcription levels were assessed in human lymphocyte samples from 1240 adults participating in the San Antonio Family Heart Study, using the Sentrix Human-6 Expression Beadchip. Lymphocytes were surveyed, as it has been proposed that their expression levels may reflect those in harder to ascertain tissues, such as adipose tissue, that are thought to be more directly relevant to disease procesn was conducted to detect loci affecting RETN mRNA levels. We obtained significant evidence for a QTL influencing the RETN expression (LOD score 10.7) on chromosome 19p. This region is orthologous/homologous to the region previously localized on baboon chromosome 19. The strongest positional candidate gene in this region is the structural gene for resistin, itself. We also found evidence for a QTL influencing resistin protein levels (LOD score 5.3) on chromosome 14q. This differs from our previously reported QTL on chromosome 18 in baboons. The different QTLs for circulating protein suggests that post-translational processing and turnover may be influenced by different or multiple genes in baboons and humans. The parallel findings of a cis-eQTL for RETN mRNA in baboon omental tissue and human lymphocytes lends support to the strategy of using lymphocyte gene expression levels as a surrogate for gene expression levels in other tissues.

Genome-wide scan revealed genetic loci for energy metabolism in Hispanic children and adolescents.

OBJECTIVE: Genome-wide scans were conducted in search for genetic locations linked to energy expenditure and substrate oxidation in children. DESIGN: Pedigreed data of 1030 Hispanic children and adolescents were from the Viva La Familia Study which was designed to investigate genetic and environmental risk factors for the development of obesity in Hispanic families. A respiratory calorimeter was used to measure 24-h total energy expenditure (TEE), basal metabolic rate (BMR), sleep metabolic rate (SMR), 24-h respiratory quotient (24RQ), basal metabolic respiratory quotient (BMRQ) and sleep respiratory quotient (SRQ). Protein, fat and carbohydrate oxidation (PROOX, FATOX and CHOOX, respectively) were also estimated. All participants were genotyped for 384 single tandem repeat markers spaced an average of 10 cM apart. Computer program SOLAR was used to perform the genetic linkage analyses. RESULTS: Significant linkage for TEE was detected on chromosome 1 near marker D1S2841, with a logarithm of the odds (LOD) score of 4.0. SMR, BMRQ and PROOX were associated with loci on chromosome 18, 17 and 9, respectively, with LOD scores of 4.88, 3.17 and 4.55, respectively. A genome-wide scan of SMR per kg fat-free mass (SpFFM) peaked in the same region as SMR on chromosome 18 (LOD, 5.24). Suggestive linkage was observed for CHOOX and FATOX. Several candidate genes were found in the above chromosomal regions including leptin receptor (LEPR). CONCLUSION: Regions on chromosomes 1, 9, 17 and 18 harbor genes affecting variation in energy expenditure and substrate oxidation in Hispanic children and adolescents.

Genetics of variation in adiponectin in pedigreed baboons: evidence for pleiotropic effects on adipocyte volume and serum adiponectin.

To detect and localize the effects of genes influencing variation in adiponectin mRNA and protein levels, we conducted statistical genetic analyses of circulating concentrations of adiponectin and adiponectin (ADIPOQ) mRNA expression in omental adipose tissue in adult, pedigreed baboons (Papio anubis). An omental adipose tissue biopsy and blood sample were collected from 427 baboons from the colony at the Southwest Foundation for Biomedical Research, San Antonio, TX. Total RNA was isolated from adipose tissue and adiponectin mRNA levels were assayed by real-time, quantitative reverse transcriptase-PCR. Adiponectin, insulin, glucose, cholesterol, high-density lipoproteins and triglycerides were measured in fasting serum. Quantitative genetic analyses were conducted for adiponectin mRNA and serum protein using a maximum likelihood-based variance decomposition approach. A genome-wide linkage analysis was conducted using adiponectin mRNA and protein levels as phenotypes. Significant heritability was estimated for ADIPOQ mRNA levels (h2=0.19+/-0.07, P=0.01) and protein levels (h2=0.28+/-0.14, P=0.003). Genetic correlations were found between adiponectin protein and body weight (rho(G)=-0.51, P=0.03), cell volume (rho(G)=-0.73, P=0.04), serum triglycerides (rho(G)=-0.67, P=0.03), and between adiponectin mRNA and glucose (rho(G)=0.93, P<0.01). A logarithm of odds score of 2.9 was found for ADIPOQ mRNA levels on baboon chromosome 4p, which is orthologous to human 6p21. There is a significant genetic component affecting variation in the analyzed traits, and common genes may be influencing adiponectin expression, adipocyte volume, body weight and circulating triglycerides. The region on 6p21 has been linked to diabetes-related phenotypes in human studies.

Linkage analysis of circulating levels of adiponectin in Hispanic children.

INTRODUCTION: Adiponectin, a hormone produced exclusively by adipose tissue, is inversely associated with insulin resistance and proinflammatory conditions. The aim of this study was to find quantitative trait loci (QTLs) that affect circulating levels of adiponectin in Hispanic children participating in the VIVA LA FAMILIA Study by use of a systematic genome scan. METHODS: The present study included extended families with at least one overweight child between 4 and 19 years old. Overweight was defined as body mass index (BMI) 95th percentile. Fasting blood was collected from 466 children from 127 families. Adiponectin was assayed by radioimmunoassay (RIA) technique in fasting serum. A genome-wide scan on circulating levels of adiponectin as a quantitative phenotype was conducted using the variance decomposition approach. RESULTS: The highest logarithm of odds (LOD) score (4.2) was found on chromosome 11q23.2-11q24.2, and a second significant signal (LOD score=3.0) was found on chromosome 8q12.1-8q21.3. In addition, a signal suggestive of linkage (LOD score=2.5) was found between 18q21.3 and 18q22.3. After adjustment for BMI-Z score, the LOD score on chromosome 11 remained unchanged, but the signals on chromosomes 8 and 18 dropped to 1.6 and 1.7, respectively. Two other signals suggestive of linkage were found on chromosome 3 (LOD score=2.1) and 10 (LOD score=2.5). Although the region on chromosome 11 has been associated with obesity and diabetes-related traits in adult populations, this is the first observation of linkage in this region for adiponectin levels. Our suggestive linkages on chromosomes 10 and 3 replicate results for adiponectin seen in other populations. The influence of loci on chromosomes 18 and 8 on circulating adiponectin seemed to be mediated by BMI in the present study. CONCLUSION: Our genome scan in children has identified a novel QTL and replicated QTLs in chromosomal regions previously shown to be linked with obesity and type 2 diabetes (T2D)-related phenotypes in adults. The genetic contribution of loci to adiponectin levels may vary across different populations and age groups. The strong linkage signal on chromosome 11 is most likely underlain by a gene(s) that may contribute to the high susceptibility of these Hispanic children to obesity and T2D.

Quantitative trait locus on chromosome 12q14.1 influences variation in plasma plasminogen levels in the San Antonio Family Heart Study.

Plasminogen is a hemostasis-related phenotype and is commonly implicated in thrombotic and bleeding disorders. In the San Antonio Family Heart Study (SAFHS), we performed to our knowledge the first genomewide linkage scan for quantitative trait loci (QTLs) that influence the level of plasminogen. The subset of the SAFHS population used for this study consists of 629 individuals distributed across 26 extended Mexican American families. Pedigree-based variance component linkage analyses were performed using SOLAR. The mean plasminogen level was 114.94% +/- 17.8 (range, 42-195). The heritability (h2) of plasminogen was 0.43 +/- 0.08 (p < 6.3 x 10(-13)). One region on chromosome 12 (12q14.1) showed suggestive evidence of linkage (LOD = 2.73, nominal p < 0.0002, genomewide p = 0.0786) near marker D12S1609. Because plasminogen has important effects in many human health problems, such as cancer and atherosclerosis, the role of this putative QTL in the regulation of plasminogen variability needs to be studied further.

Meta-analysis of five genome-wide linkage studies for body mass index reveals significant evidence for linkage to chromosome 8p.

OBJECTIVE: To perform a meta-analysis of genome-wide linkage scans using body mass index (BMI) to identify genetic loci predisposing to obesity. DATA: A total of 13 published genome scans on obesity have used BMI as their primary end point. Five of these 13 groups agreed to provide detailed results from their scans that were required for a meta-analysis. Collectively, these five studies included a total of 2814 individuals from 505 families. METHODS: The results of the five studies were analysed using the GSMA (genome scans meta-analysis) method. RESULTS: The analysis revealed significant evidence for linkage of the quantitative phenotype BMI to 8p (P<0.0005).

Genome-wide scan of resistin mRNA expression in omental adipose tissue of baboons.

INTRODUCTION: The hormone resistin was recently discovered in adipose tissue of mice. Functional tests suggest a role for resistin in the regulation of insulin sensitivity. However, human studies have reported controversial results on the metabolic function of this hormone. METHODS: A 1 g omental adipose tissue biopsy was obtained from 404 adult baboons. Resistin mRNA expression was assayed by real-time, quantitative RT-PCR, and univariate and bivariate quantitative genetic analyses were performed, via the variance decomposition approach. A genome scan analysis was conducted using resistin mRNA abundance in omental adipose tissue as a quantitative phenotype. RESULTS: A significant heritability of h2 = 0.23 (P = 0.003) was found for resistin mRNA abundance in omental adipose tissue. A genome scan detected a quantitative trait locus for resistin expression with an LOD score of 3.8, in the region between markers D19S431 and D19S714, corresponding to human chromosome 19 p13. This chromosomal region contains genes related to insulin resistance phenotypes, such as resistin, insulin receptor, angiopoietin-like 4 protein and LDL receptor. CONCLUSIONS: Individual variation in resistin mRNA expression has a significant genetic component, and a gene or genes on chromosome 19 p13 may regulate resistin mRNA levels in baboon omental adipose tissue.

Variation in menstrual cycle length and cessation of menstruation in captive raised baboons.

Primatologists have recognized that non-humans undergo the menopause [Biol. Reprod. 68 (2003) 10], which is preceded by years of irregular cycles and decreased fecundity. The similarity of reproductive changes between humans and baboons suggests that the aging female baboon is a particularly promising model to study human menopause and changes that precede it. In an effort to provide an assessment of potential peri-menopausal changes in reproductive function in non-human primates, our goals were to determine if menstrual cycles become more variable with age and to identify the onset of changes consistent with peri-menopause and menopause in baboons. To accomplish these goals, we calculated means and variances for menstrual cycle lengths of females at ages 5, 10, 15, and 20 years and identified onset of menstrual cycle variability (peri-menopause) and cessation of menstruation (menopause). Mean cycle lengths were not significantly different, but significant heterogeneity of variances existed, with younger animals experiencing less variability than older animals. Mean ages of onset for the peri- and menopausal transitions were 18.89 and 26.34 years, respectively. These results provide evidence that captive aging female baboons experience menstrual cycle changes similar to peri- and menopausal women.

Genetics of leptin expression in baboons.

OBJECTIVE: Leptin gene expression is higher in females than in males, and is regulated by many factors including energy intake and insulin, but little is known about the inheritance of leptin gene expression. We have investigated leptin (LEP) gene express-ion, to determine whether it is heritable, and whether the difference in LEP expression between males and females has a genetic component. STUDY POPULATION: A total of 319 baboons (Papio hamadryas) (220 females, 99 males) from a captive, pedigreed colony. MEASUREMENTS AND METHODS: We cloned a baboon LEP cDNA, and quantified LEP mRNA expression in baboon omental adipose tissue using a ribonuclease protection assay. In addition, we assayed circulating leptin levels, adipocyte cell volume, and weight. We used maximum likelihood-based variance decomposition methods to determine the genetic architecture of LEP levels, including testing for genotype-by-sex interaction. RESULTS: Omental LEP mRNA expression was significantly and positively correlated with weight and adipocyte cell volume in baboons. Both mRNA and plasma levels of leptin were higher in females than in males, and both measures were heritable. The results of our genetic analysis show that there was a genotype-by-sex interaction in the levels of plasma leptin, but not in omental LEP mRNA. CONCLUSIONS: As in humans, baboon leptin mRNA and protein levels are expressed at a higher level in females than in males. We detected evidence that the plasma levels were affected by genes that are differentially expressed in males and females, while the omental mRNA levels were not. This finding suggests that the genes that differentially regulate plasma leptin levels between males and females may exert their effects on post-transcriptional processes.

Genotype-by-smoking interaction for leptin levels in the Metabolic Risk Complications of Obesity Genes project.

RATIONALE: Recently, we identified a genotype-by-smoking status interaction with serum leptin levels in a sample of Mexican Americans. However, it is unknown whether this phenomenon occurs in other populations as well. OBJECTIVE: The goal of this study was to examine the genetic architecture of the response to smoking in leptin levels using data from Midwestern Caucasian subjects participating in the Metabolic Risk Complications of Obesity Genes project. METHODS: We employed a variance decomposition analysis using maximum likelihood methods to model genotype-by-smoking interactions for leptin levels and examined the impact of the exclusion of smokers in a subsequent linkage analysis. RESULTS: We found significant evidence (p-value=0.027) for a genotype-by-smoking status interaction for serum leptin levels. In the subsequent linkage analysis with smokers excluded, we obtained a maximum LOD score of 3.4 (P=0.00004) near D8S1128. CONCLUSIONS: These results suggest that a QTL on chromosome 8 may have a differential effect on the expression of leptin in smokers vs nonsmokers, as first identified in Mexican Americans.

Genetic control of coordinated changes in HDL and LDL size phenotypes.

We investigated the correlation of high density lipoprotein (HDL) and low density lipoprotein (LDL) particle size distributions in samples from >1100 participants in the San Antonio Family Heart Study. By use of analyses of individual correlations of each HDL fraction with each LDL fraction, we devised new metrics for particle size phenotype, termed DeltaHDL and DeltaLDL, to optimally reflect the size correlations. Confirming previous studies, we found that the 2 size phenotype variables were positively correlated (r=0.51). Quantitative genetic analysis indicated that nearly half (44%) of the variance in DeltaHDL and in DeltaLDL was explained by the additive effects of genes. Bivariate genetic analyses indicated that a positive genetic correlation (rho(G)=0.56) exists between them and suggested that the pleiotropic effects of a gene or group of genes account for approximately 31% [ie, rho(G)(2) =(0.56)(2)=0.31] of the genetic variance in the 2 traits. Triglyceride (TG) levels were negatively related to DeltaHDL and DeltaLDL, with phenotypic correlations of -0.48 and -0.58, respectively, and genetic correlations of -0.45 and -0.76, respectively, suggesting that genes exert significant pleiotropic effects on the covariation of TGs with each of the size variables. Finally, we evaluated a bivariate model for DeltaHDL and DeltaLDL in which TG level was included as a covariate. This analysis indicated that a small but significant genetic correlation remains for DeltaHDL and DeltaLDL, even after accounting for the effects of TGs. Thus, our study demonstrates that the phenotypic correlation of HDL and LDL sizes results in part from the pleiotropic actions of a set of genes, some of which also influence TG levels and some of which do not.